March 2, 2023

From podcast: https://bengreenfieldlife.com/podcast/gregory-kelly-senolytic/

[00:00:00] Introduction

[00:01:10] Podcast Sponsors

[00:06:38] Introduction to Dr. Gregory Kelly

[00:10:10] The science behind cellular senescence

[00:19:15] The use of senolytics

[00:27:53] Other strategies that can limit senescence

[00:32:09] Podcast Sponsors

[00:36:24] cont. Other strategies that can limit senescence

[00:39:39] Senolytic formula from Neurohackers

[00:56:46] Adaptogens included in formula

[01:01:15] Tonic herbs

[01:06:20] The efficiency

[01:13:25] Shine Sedona

[01:14:27] End of Podcast

Ben:  My name is Ben Greenfield. And, on this episode of the Ben Greenfield Life podcast.

Gregory:  Identifying and studying senescent cells is pretty hard. Really, you have to do tissue biopsies to identify senescent cells in tissues. So, because of that, there just hasn't been the amount of research on things that would be in that hormetic category for how they impact senescence. But, intuitively because these stressors are known to be a big part of this premature cellular senescence or stress-induced senescence, my guess is that a lot of the things that we're trying to protect ourselves from by being biohackers and integrating these hermetic habits into our lifestyles would help at least slow down the accumulation of senescent cells.

Ben:  Faith, family, fitness, health, performance, nutrition, longevity, ancestral living, biohacking, and a whole lot more. Welcome to the show.

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Alright. So, it's no secret that everybody, at least most people I know, kind of want to slow down the signs of aging, but a lot of people are not going about it the right way because they aren't actually paying attention to what's called senescence, cellular senescence. Now, senescent cells, as my guest on today's podcast is going to fill you in on in great nitty gritty detail, are these cells that can accumulate in the body and accelerate aging. You get more of them as you get older. There are ways to get rid of them, so-called senolytics, and that's actually what my guest, Dr. Gregory Kelly, kind of specializes in. How do you clean up these senescent cells? How are they a problem in the first place? What do you do about them? And, how do you ultimately live longer and have better health span and lifespan based on what you do.

Now, Greg is not only a naturopathic physician, he also develops products for Neurohacker Collective. That's a company that actually makes a nootropic, smart drug kind of formula that I really like. Even wrote a book called “Shape Shift,” “Shape Shift.” And, he studies nootropics, anti-aging, regenerative medicine, weight management, chronobiology, which is kind of circadian rhythm type of stuff. He has more than 30 different journal articles indexed on PubMed. He's published various articles on various aspects of natural medicine and nutrition. And so, he's wealth of knowledge. He's never been on the show before, so we'll see how this goes. You never know with a first-time guest. But, anyways, everything that you hear is going to be at BenGreenfieldLife.com/Senolytic. I know that's hard to spell, so I'm going to spell it for you, S-E-N-O-L-Y-T-I-C, BenGreenfieldLife.com/Senolytic is where you can grab the shownotes.

So, Greg, welcome to the show. Are you ready to talk about these so-called zombie cells?

Gregory:  Yeah, really excited today to share this with you and your audience.

Ben:  Yeah. Does that annoy you by the way when people call senescent cell zombie cells? Because everything in the body has a reason, and this is really something I want to ask you anyways. It's not like senescence is totally bad, right?

Gregory:  No, no, there's like most things, and you're well aware of this, context matters. So, we'll get into a deep dive on that. But, to answer your question, no, I think zombies is a good analogy for senescent cells, especially what we'll really talk about the subtype of them that accumulates as we get older. And, the reason is twofold, there are cells that haven't died and can turn other cells into senescent cells. So, very akin to what you'd see in zombies in a movie or a book.

Ben:  Okay. So, basically, they can be cells that are almost dead like a zombie not quite dead, and wreaking havoc in the human body to use the highly scientific terminology.

Gregory:  Absolutely, yes. So, I think it's why I think it's the most widespread metaphor. At Neurohacker Collective, we tend to go more for a gardening analogy and yellowing leaves and being a gardener and pruning senescent cells away. But, it would still have some analogies. A gardener as an example with leaves yellowing on a plant. There's a couple different issues that cause this. One, they can be a source to spread disease now to other more vibrant leaves. They use up resources. And, while they're there, you can't promote new growth. So, in a sense, senescent cells would do those things in our tissues as well. And so, I generally use that gardening yellowing leaves analogy instead of zombies, but they're both very appropriate.

Ben:  Yeah. I guess it just depends if you're a green thumb person or a movie freak.

The idea with the cell senescence is that these cells, from what I understand, they stop dividing, right? Cellular senescence is just the cessation of cell division. And, I know there's a lot of stuff that can cause the cells to stop dividing like stress and oxidation and environmental toxins and things like that. But, it kind of begs the question, why would the body have this built-in mechanism in the first place? And, the reason I asked that is where my mind goes unhampered cellular division with no breaks on it would technically be something that we'd kind of call cancer, like this full-on growth of cells with no breaks, whatsoever. And so, would cell senescence be built in as a mechanism in the body to keep us from getting cancer or something like that?

Gregory:  Yeah, it's definitely thought of as a stress response program. So, I guess going back in time, the origin of the idea of what's now known as cellular senescence goes back to Hayflick in 1961. So, before his work, there was this thought that if you put cells in a culture and as long as you gave them enough food and created a hospitable culture environment, they would just be immortal, they would grow forever. And, what Hayflick found is that human cells, and they were fibroblasts that used in that study, divided about 50 times before they essentially hit a wall. It wouldn't divide any further. So, that's now known as the Hayflick limit.

Ben:  Okay.

Gregory:  And, that introduced this idea of cellular senescence, this idea that cells can get to a point with certain amounts of divisions where they'll just frankly say “I'm done, I'm not going to divide anymore and make any new cells.” Leaping forward to the '70s, the idea of telomeres or telomeres depending on, I guess, the pronunciation, one's more British, one's more North American, were identified and became eventually known that it was the shortening of telomeres over time. As cells copied themselves, that would cause this running into the Hayflick limit. 

And, kind of one of the other things about the Hayflick limit it varies organism to organism probably also even in humans, tissue to tissue. So, that idea, we could call replicative senescence. And, my guess is that's at most really minor importance in aging. We fundamentally even older people don't run out of the ability to create new cells and to have cell proliferate. But, because of this kind of clock with telomere attrition ticking down, shortening, shortening, shortening, there became this idea that senescent cells, that mechanism replicated of senescence was probably a pretty prominent part of aging. 

And so, now, we're back in [00:12:59] _____ 2010. And, what eventually they, I guess early on, thought is, okay, well, these cells are–so, I guess telomere attrition in a simple sense would subject DNA to potential damage if it's copied. So, cells in that, this program called DNA damage response. So, the general idea was, okay, this makes sense, we shouldn't copy these cells if we might be copying damaged DNA because that could promote cancerous cells. So, this idea that senescent cells or cellular senescence was an anti-cancer mechanism was fairly early on in the senescence thing.

Now, as times evolved and especially more recently, it's really nuanced. And so, this is going to be way oversimplified but just so we don't get too bogged down. When cells are pre-cancerous, enacting the cellular senescence programs probably beneficial in terms of preventing cells from going towards a damaged cell that could just copy itself over and over and over become cancerous. But, once cancer is developed, especially in older organisms, cellular senescence is probably a net negative. So again, by context.

Ben:  Okay. So, would that mean–because this is something I've been thinking about a little bit when it comes to senescence, it's kind of the idea with protein. We don't necessarily want, especially later on in life, to excessively stimulate mTOR, for example, or excessively cause anything that would result in pro-growth functions that might potentially cause cancer. And, I'm not saying that older individuals can't benefit from growth hormone precursors or peptides that simulate growth hormesis or amino acids and forms of protein and enzymes that break down protein that allow them to better assimilate those amino acids. But, at the end of the day, it appears that longevity is assisted with some amount of slowing down this pro-growth effect. Yet, at a younger age, when fertility and muscle and a lot of things related to performance and replication of the human species should be prioritized, then we would actually want to really be engaged in a lot of pro-growth activities that might accelerate aging later on in life.

So, that being said, let's say–and, I know we'll get into these so-called senolytics that can get rid of senescent cells later on in our chat, but if you're young, should you be thinking twice about trying to shut down senescence so that you're able to grow and be fertile and everything?

Gregory:  What I would generally bucket senescence into, so I mentioned, is the replicative senescence, the Hayflick's limit. But, depending on what causes a cell to become senescent basically to execute the software program, the cell will have really almost different structure and function. So, several other areas where senescence is at least in the right amount good, one would be the embryogenesis, so the development in utero. Another would be placental aging. So, there's at least some research that suggests that senescence in the placenta, and this would be, I guess, somewhat controversial, but would be involved in the age of placental aging. But, for sure in these animal experiments, it has to do with triggering labor.

So, pregnancy, as an example, would be a time period where in general I'm a believer in the precautionary principle, if something's not known to be safe in something like pregnancy, then you just wouldn't do it. So, senolytics, I would say, would be something during pregnancy, you have no reason to take down potential downsides because senescent cells are definitely doing a few useful things during that time period.

Wound healing would be another area where senescent cells are known to play a role. But, even in that, it's more of a timing issue. So, in both the embryogenesis and in wound healing, think of it as a wave of senescent cells come in early on to do something good. So, this senescent cell post, say like you just ran a marathon that's quite a bit of muscular trauma, inflammation caused him that, there would be some need to repair and regenerate. So, there'll be a wave of senescent cells that'll sweep in. They help attract macrophages, other aspects of the immune system to do the repair regeneration. And, a week later, they have been cleaned up either by going through a falling off process called apoptosis or by the immune system coming in and scavenging up, gobbling up any remaining senescent cells. 

What would be problematic is if that wave came and didn't recede and the senescent cells lingered, then instead of helping the tissue repair and heal itself, it would actually hinder that.

Ben:  Okay.

Gregory:  Right. So, because of that, I tend to use this idea of there's transient senescent cells mostly beneficial, have a role, doing a job, and then there's lingering ones, which are most of the times causing issues.

Ben:  Okay. So, what it sounds to me in a nutshell is that for the most part, senescent cells are going to cause damage to the body and accelerate the onset of chronic disease due to the inflammation and there may be some other things that they're causing that I love to hear in terms of what type of damage a senescent cell is actually causing. But, at the same time, if you are pregnant, if you are potentially trying to heal a wound, I don't know, maybe your burn victim or something like that, if you have an existing tumor and maybe if you're trying to repair a whole bunch of muscle damage, I don't know, maybe if you're a bodybuilder or something, then taking senolytics could potentially not be a good idea. But, if you don't fall into those categories from a longevity or anti-aging standpoint, having some form of a senolytic strategy could be a good idea.

Gregory:  I think that's fair. And, that's how I would bucket it. But, even say for the bodybuilder, periodic senescent or senolytic, senescent clearance strategies might be advantageous. Maybe not in the couple days after something that you really put a lot of trauma on the muscles, but intermittently, I think would be potentially prudent.

Ben:  A lot of the studies that I've seen, particularly on pharmaceuticals for getting rid of senescent cells actually do, because you just mentioned not doing it all the time, it seems that they have these pulses a few times during the year that you would take senolytics, but it's not something you would use every day. Is that correct?

Gregory:  Yeah. And, the way I think of it–have you had Valter Longo on your show before?

Ben:  No. No, he's the fasting-mimicking diet guy, right?

Gregory:  Yeah, yeah. So, he was on our Collective insights at one point. So, the fasting-mimicking diet just to give context is something meant to replicate short periods of fasting. So, his original research going back to mice, I believe, he would fast mice completely for two or three days. And, some of the changes that he noticed would be it would promote autophagy, which is a different than senescence, different than apoptosis, but another cellular response program. And, it would also tend to selectively get rid of cells that were stressed like senescent cells, particularly. I believe he was measuring senescent immune cells like macrophages.

And so, he created that fasting mimicking diet as a way to get the upside of short periods of fasting without some of the downsides, because at the time, I think, he was doing a lot of research with cancer patients and it was hard for some of them to even do a three-day water fast. So, when I think of senolytics, especially in the sense of Qualia Senolytic, the product that Nuerohacker Collective created, these are things that are essentially mimicking short periods of fasting, is how I would say they work based just mechanistically. And so, because of that, just like you wouldn't want to go on a water fast every day for the rest of your life, doing senolytic compounds, generally speaking, is also something that's short periods like bursts to just mimic a signal, and then let that signal take its role in the body, turning on and off genes, causing certain cells that are less important like potentially senescent cells to then go through this falling off process.

Ben:  Okay. Did you see the study, and I'm sure somebody who's looked into senescent cells, you probably did on I think it was the dasatinib, I don't know if I'm not pronouncing that properly, with quercetin as this one-two combo stack. At least that's the one that I've seen talked about a lot in the anti-aging and longevity circles as kind of what was the gold standard based on research to limit senescence. What do you think about that?

Gregory:  So, the idea of senolytic was coined by Mayo Clinic and Scripps, Institute of Aging, researchers in 2015. And, the original stack that they identified was I would say dasatinib, but I'm not sure that that's the correct pronunciation either, and quercetin. And, that combination was interesting because, I guess stepping back, senescent cells are a category of things that all have in common this idea that they won't divide any longer. They also have some other characteristics in common, but many of the other characteristics especially when you start to think structurally and functionally can vary. So, when we talk about like that, I would say develop mental embryogenesis placenta. Those cells will have actually slightly different markers on them than these zombie cells we're talking about with HA as an example.

So, just like going back, so the insight for the Scripps and Mayo researchers was that what we wanted to do was induce these cells to go through apoptosis, which literally translates as falling off in the sense that leaves or fruit falling off of a plant. So, apoptosis is the Greek word. 

And, the idea was, okay, let's find things that mechanistically may shift the balance in cells from resistant going through that process in favor of that. And so, they identified several different candidates, eventually found that dasatinib was really useful as an example in the original research in adipose tissues, fat cells, to get some senescent fat cells to complete this journey to falling off. Quercetin wasn't active in that but was active in bone marrow and in, I think, it was endothelial cells in that research. And, the combination was active in places that each individually wasn't. So, that created that stack, which is by far the most research combination. I think, fisetin or sometimes pronounced fisetin would be second but not quite really even a close second.

Ben:  Yeah.

Gregory:  I just would say D and Q, the D&Q stack is by far the most used right now.

Ben:  Somebody gave me the D&Q stack. They gave me a few day supply if I want to try it to clear senescent cells. I didn't take it. I looked into it, and for me as an athlete, I was a little bit concerned about this because apparently, it can lower your blood cell count, and then the other side effect is diarrhea along with the anemia. And, I don't know if that's common or if that's just something you don't need to worry about with low dosages or standard dosages or something like that. But, are you familiar with side effects of that stack?

Gregory:  It's a tyrosine kinase inhibitor. That's the category of drug it's in. And, it's used particularly for blood cancers. And, definitely in that context, like a lot of anti-cancer drugs, can have fairly significant side effects. So, one of the, I guess, again, the original idea from the researchers at Mayo and Scripps was, alright, well, dasatinib may not be a great thing to have people take every day, maybe if you need to pulse it more frequently for cancer treatment, that's one thing, but let's see if we can shift this risk-reward profile in a way that we get a much better risk-reward ratio. 

And so, right from the get-go, they had this idea, well, let's do what they called hit-and-run dosing. So, instead of doing something every day, let's just do this intermittently. Let's give the D&Q stack for a couple days, give a window of time to recover for it, and then do another cycle. So, that idea of hit-and-run dosing was almost built in from the beginning as a way to take something that would otherwise not be a great thing to do in terms of at least the side effect profile, dasatinib. And, let's figure out a way to do it in something that at least seems more prudent. And so, even with natural compounds like quercetin as an example, I believe all of the studies–well, let me say, the last time I looked at clinicaltrials.gov for studies that were registered on fisetin as a senolytic, all of them were following some type of an intermittent dosing protocol.

Ben:  Yeah, yeah. And again, that seems to be the case with a lot of these senolytic agents whether the pharmaceuticals or the natural agents.

Now, another couple of things that I've seen pop up for controlling senescent cells are two other kind of darlings of the anti-aging or longevity community: metformin and rapamycin. Have you looked into those at all as a senolytic?

Gregory:  Sometimes what you'll see in the cellular senescence community is this idea of senotherapeutics. So, think of senolytics as one leg under the broader senotherapeutic category. Two other legs, one would be called senomorphics, sometimes also called senostatic or senostatics. And, the third leg of the stool would be the immune system. The idea of that middle leg, the senomorphics is, are there things we can do that would protect cells that are near these things from becoming zombies? So, rapamycin would I think classically be thought of as more xenomorphic than senolytic, if that makes sense. I mean, it impacts obviously the mTOR pathway, which is very important in senescent cell signaling as well. A big part of cell choosing to become senescent or go from senescent to that falling off process has to do with nutrient sensing in the environment.

So, I guess getting back to your question, the general idea would be or I would categorize rapamycin more as a senomorphic, something that's helping essentially toughen up cells near senescent cells to make sure they don't also become senescent. Metformin, I've seen less on and I would, again, put it more in that senomorphic area. Again, mostly because of what it's doing with nutrient signaling, but probably more on the glucose side than on the protein side like mTOR would be more amino acid signaling.

Ben:  Okay. So, based on this idea of either senolytic agents that would kill off senescent cells or senomorphic agents that would kind of transform the environment, the senescent cells are in, are there things other than say over-the-counters or pharmaceuticals or nutrients that would limit senescence? I mean, you mentioned fasting, so I assume that would fall into the category. But, what about a lot of other strategies that could exist out there like, I don't know, cold therapy or sauna or light therapy or anything like that? Have any of those type of strategies been studied?

Gregory:  Very few of them. We can jump into a couple that have. But, I guess, first, maybe we want to set kind of the backdrop. So, we talked about telomere shortening, Hayflick limit, basically replicative senescence. But, shortly–well, relatively shortly after that was identified, what they also found in these cell cultures is that lots of things could cause premature senescence, basically too much oxygen, too little oxygen, not enough nutrients, too much nutrients, ionizing radiation. So, all of these things collectively tend to be pigeonholed in this idea of premature stress-induced senescence. And, my guess is that most of what we're talking about when we think of cellular senescence aging has nothing to do with this Hayflick limit, it's these stress-induced premature senescence that cells are going through long before they've run out of the ability to divide.

So, with that backdrop, the way I loosely think of, Ben, how would a cell respond to stress, I buck it into a couple areas. So, the first thing where it's going to be upregulate antioxidant defenses, create a fitter mitochondrial network, basically toughen itself up, make itself more resilient. And, if stress is more, then it can adapt to, then it will damage some things like maybe some mitochondria, some other things inside a cell, typically proteins. So then, what it will run is autophagy, which is a cleanup stress program. Alright, let's recycle some of these damaged proteins and organelles and reuse those components to make better versions.

And, if stress is more, then could be dealt with something like with DNA repair, autophagy, that's when cellulose senescence would get activated. It's like, okay, there is enough damage that let's just freeze things where they were until we can sort it out, but not so much damage that it's tripped it into apoptosis, basically, the cell is like, okay, damage is so much, let's just get rid of this cell. And then, if damage is even more than that, that's when necrosis, I'm sure you're familiar with that idea like apoptosis would be a cellular stress program, it's very controlled when necrosis is basically trauma just cause the cell to die accidentally. And so, there's that continuum.

So, when I think of things getting back to what you asked about, cold therapy as an example or some of these other things we do to build stress resilience, my intuition is those things on the continuum are going to make cells in that first category. We've made ourselves bitter, much more capable of dealing with a wide range of other stresses. We've done something hormetic. And, some of those things may help get rid of at least senescent cells in certain tissues, but that's far less known. And, in part, it's because identifying and studying senescent cells is pretty hard that really you have to do tissue biopsies to identify senescent cells and tissues. 

So, because of that, there just hasn't been the amount of research on things that would be in that hormetic category for how they impact senescence. But, intuitively, because these stressors are known to be a big part of this premature cellular senescence or stress-induced senescence, my guess is that a lot of the things that we're trying to protect ourselves from by being biohackers and integrating these hormetic habits into our lifestyles would help at least slow down the accumulation of senescent cells.

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So, there's no lab assays that you could get that would measure your rate or volume of cellular senescence. You would literally have to do a biopsy?

Gregory:  Yeah. And, you'd have to do it in pretty much every tissue because–so, as an example, going back to that original D&Q study, there was bone marrow they looked at, endothelial cells they looked at, adipose tissue they looked at, and dasatinib was active with adipose issues not with the other ones, of course, vice versa. So, yeah, there's no simple assay. Buck Institute is one of the leading researchers in cellular senescence and senolytics. What they would typically do even in a cell culture, there's no one thing they can look at in that culture and say, okay, this is a senescent cell and this isn't. Now, senescent cells to a trained eye might look slightly different, so they could potentially visibly see a difference in some. But, what they'll usually look for is an enzyme-coil beta-galactosidase that senescent cells tend to give off that enzyme, but it's not a 100% sensitive for senescent cells. So, they'll stain cells for that. I believe if they turn blue with the right stain, that's a mark and that, oh, this enzyme's disproportionately in this cell. But then, they'll look for other markers like P16 is a good one, which is a protein that some cells give off. So, cells are positive for P16. They're much more likely to be a senescent cell. So, fundamentally what the scientists would do is they would look for cells that have a grouping of characteristics.

Ben:  Yeah, yeah. Well, based on the fact that you see a high secretion of pro-inflammatory cytokines and higher levels of inflammation with senescence, you could probably at least do–because it'd be pretty easy to get a blood inflammation analysis of levels of homocysteine and fibrinogen and CRP and a host of other inflammatory markers, and that might give you a clue at least that you might have a high rate of cellular senescence, yeah?

Gregory:  Correct. There's a lab in Atlanta called Jinfiniti that has a blood panel, and that's what they're looking for. They're looking for beta-galactosidase, they're also looking for these inflammatory cytokine markers in the blood. Last time that I talked with the founder there, they were also looking at NAD, the idea being because inflammation tends to gobble up a lot of NAD, that NAD might be an indirect way of guessing as whether there's a big burden of senescent cells and tissues throughout the body.

Ben:  Okay. So, do you think that if someone were taking NAD that would be one good anti-cellular senescent strategy?

Gregory:  Yeah. I think at least to some extent, NAD or NAD boosters would be, again, thought of as being in that xenomorphic category things that if the cell doesn't have enough NAD, so mitochondrial dysfunction, as an example, would be one of the things known to cause premature cellular senescence. So, things that support healthy and mitochondria and NAD would be in that category would tend to make a cell, again, fitter so that it can resist stress and not execute this senescent cell program.

Ben:  Okay, got it.

Now, there are a wide variety of compounds that I see that you've looked into in this analytic formulation you guys have been working on. You actually sent me some, I think it was two months ago, it came in this little white box. And, the instructions were just to take the pills. I forget how many there were. Wasn't that small number. How many pills were there?

Gregory:  Yeah, daily dose is six capsules.

Ben:  Yeah. So, you take six capsules on day one, six capsules on day two, and then you're just kind of done. And so, I tried that, I just did one. From what I understand, the protocol is you're supposed to do two days out of the month every month, yeah?

Gregory:  Yes, that's our general recommendation. We've done two small pilot studies where we had people do it more frequently than that. So, we did three cycles over the course of about a month. So, two days on, 12 days off, two days on, 12 days off. So, that's the most frequent that I would have anyone do it. And, the most, I guess, slowest amount I would recommend would be to do the two days once a quarter. But, our general recommendation and what we use ourselves is the once a month two days.

Ben:  And, have you been getting results back from people in terms of anything like heart rate variability or telomere length or these DNA methylation clocks or anything like that?

Gregory:  Telomere length, I wouldn't expect to have anything to do with–again, that's that Hayflick limit, a very different type of that replicative senescence. So, I don't think that would be a useful marker. I've talked to Ryan Smith at TruAge, some people at Clock Foundation, the GrimAge, epigenetic tests using DNA methylation, and then some people in the longevity community. But, the consensus is that DNA methylation is just not a useful way to measure senescent cells because senescent cells just don't exhibit the same types of DNA methylation patterns. So, what we've opted for is to then tend to look much more subjective thing. So, as an example because it's so hard to directly measure senescent cell short of taking biopsies, some of the pharma companies that are developing their own senolytic, in this case, drug candidates have tried to figure out ways to look at things.

So, again, what you suggested, inflammatory markers in the blood is one that is in some studies. But, several studies have looked at. Do you know the WOMAC scale? Is that a scale you've ever run across in research?

Ben:  No, tell me about it.

Gregory:  So, WOMAC is, I think, it's Wisconsin Ontario–I can't remember the rest of it, but it's basically an osteoarthritis scale.

Ben:  Like a pain scale?

Gregory:  Yeah. Pain, activities to daily living, so ease of getting in and out of cars, going up in stairs, things like that, as well as some areas of flexibility. So, that's widely used in anything to do with joint pain. So, you'll find studies of glucosamine that use the WOMAC scale and the same with lots of medication. So, several of the senolytic studies registered on clinicaltrials.gov use that and then recruit people with some degree of osteoarthritis. So, that idea of subjective, is this make making a difference in your ability to do activities to daily living, has been fairly common just as a default thing since there's no great easy blood marker for it. And so, what we tend to focus on especially because in the supplement world as you would well know, so we're really limited in terms of what types of claims we can make to structure-function. So, we have to avoid things that would be preventing treating disease.

So, what we at Neurohacker Collective do is we'll recruit people and then we'll have them do some type of validated questionnaire that looks at things that would be more the positive characteristics of healthier age like are you better able to perform activities of daily living after a few cycles of Qualia Senolytic. And, we've seen positive results in that, we've seen positive results in areas of energy, emotional, well-being, stress in general. And then, individually, I think senescent cells can impact different people quite differently. That's definitely true in research. And, part of the reason they think so would be this idea of a threshold effect. So, below a certain amount of senescent cells in tissue, other mechanisms may accommodate enough so that we're not subjectively or objectively experiencing the negative effect of the growing amount of the equivalent of yellow leaves in that tissue but once we cross that threshold then they're much more problematic. And so, that also makes it's very individual how it's experienced because, I mean, I'll be 61 next month, but at least I feel I'm a pretty healthy 61. I'm not limited. I don't have things consistent with inflammaging. So, how I might experience it might be vastly different than someone that's my age 60 and that's much more limited.

Ben:  Okay. Yeah, that makes sense. I want to get into some of the ingredients that you have in this senolytic formula because I hadn't seen some of these before. And, a lot of them like a lot of compounds that you'll find in supplements they have their special brand name and then the actual ingredient is revealed later. But, one that left out to me right off the bat obviously was this thing called Senactive because I think you have what, was it 10 or so ingredients in this formula?

Gregory:  Ten if you count that as two.

Ben:  Okay.

Gregory:  And, it would be fair to do that because it's a brand ingredient but it has two compounds in it. One is notoginseng, which is used very prominently in Chinese traditional medicine, and then a sweet rose chestnut extract would be another part of Senactive.

Ben:  Okay. So, what do those do?

Gregory:  The company that has made and studied Senactive has done about 10 studies on it, some in vitro, some in animals, and some in humans. But, the human ones have focused on exercise. So, the Senactive originally was positioned as something to take acutely before exercise to help recovery. What they then found is that–and, I guess stepping back, so I mentioned stress of all types can cause some senescent cells. You and I talked about earlier that senescent cells, the transient ones also play a role in wound healing, things like that, repair, regeneration. So, one of the things with intense exercise is that we'll naturally create some senescent cells. Because of that, the company that makes Senactive, at one point, decided, well, let's just look post-exercise in people that have taken Senactive or Placebo to see how quickly the senescent cells that are made are cleared. And, what they found is that they were cleared much more efficiently in people that took Senactive. So, you have this on one side this ingredient that's positioned as exercise recovery better performance and then one of its mechanisms just turned out it helped get rid of senescent cells in muscle tissues.

And, one of the reasons, I think, that's super important with age is sometimes it's called anabolic resistance. But, think of akin to insulin resistance. As we get older, muscles become much more resistant to the same things that would stimulate much better growth in a 20-year-old. As an example, exercise, but also protein intake. And so, one of the studies, I think, that was really cool and I've seen another group replicate it is that this anabolic resistance in old mice. So, what they did in this particular study is they had young mice, old mice, had both intense exercise, looked for senescent cells after. And, within, I think, it was seven days and the young mice, all the senescent cells had been cleared out, they did their job and they were gone. But, in the old mice, two weeks later, there was still a bunch of lingering. And, in that particular study, they gave the D&Q stack to the old mice and it got rid of that and helped rejuvenate the muscle tissue, so everything from fibers to hypertrophy.

I think one of the big challenges with aging is we're all going to have this anabolic resistance. And so, things that might support our muscle in getting rid of lingering senescent cells to me makes just a lot of sense, hence it's Senactive.

Ben:  Okay. So, Senactive is basically ginseng and sweet chestnut rose. It's two different things used in traditional Chinese medicine.

Gregory:  Yeah. And, specifically, notoginseng, which is in the Panax family but different than Panax ginseng.

Ben:  Okay, got it. Now, you mentioned that something like the ginseng could be useful for staving off sarcopenia or muscle loss, if I were to take your senolytic ingredient, is there a proper timing? Should I go work out after I take it on those two days out of the month? Should I prioritize getting a good strength training session? You'd also mention that some strategies like fasting might pair well with senolytic agents? So, should I instead fast and go easy? Or, is there a gold standard activity level that someone should have on the two days that they take this stuff?

Gregory:  So, I wouldn't pretend to know that. I can just have my intuitions and things I've self-experimented with and know some other people. But, getting to Senactive, specifically, they've done that acutely before intense exercise. So, I don't think that matters. Personally, if I had done intense exercise a few days later, maybe after a week would be when I would time the senolytic. But, just to make it easy on myself, I know I do it the first weekend of every month, it's just easier to put into my protocol at that point in terms of then stacking other behaviors. I do know some people that have done it on days that they're doing maybe their monthly as an example, fasting behavior where they're doing a water fast or something more into the fasting-mimicking diet. I've done that too. I've done it on times where I don't do that. And, I don't think anyone really knows is there and to what degree there might be advantages of stacking things or timing things differently.

And so, what I tend to go back to is Longo's work, the fasting-mimicking diet person. So, one of the things that he reported pretty early on, and again, this was before he would have come up with what became known as the fasting and making diet, but just had animals that were water fasting for a few days. And, his lab was very focused on cancer and autoimmunity, but some of the cancer studies would have been found that, okay, you do this short fasting for a couple days. And, what that does, again, promote autophagy. He almost described it as for healthy cells, it would almost be putting a shield around them. It would make them more stress resilient. But, for cells that were already maybe on the tipping point of, I'm senescent, should I or shouldn't I go through this falling off process? It would tip them into apoptosis, the same with more damage cells than senescent cells.

And so, then the aftermath of that in the recovery, one, you would make regrow better cells, but two, the unhealthy cells, so, in that case, the cancer cells, were much more susceptible to the chemotherapy than they would have been before doing this short fasting window. So, when I tend to think of the Qualia Senolytic, I personally think of it as something that's more mimicking this idea of a short fast. And, this is a complete guess. So, one of the pathways that things like fisetin, quercetin, luteolin, Qualia Senolytic are known to impact, it's the PI3K, AKT, mTOR pathway, so it's a nutrient signaling pathway. And, there's also an mTOR direct through amino acids. But, this pathway, my intuition and I could be so wrong in this, but evolutionarily when would your guess be that we would have consumed potentially a lot of things like fisetin, quercetin, much more than in a normal diet.

Ben:  Well, thinking seasonally, I don't know, during the spring and summer?

Gregory:  That's probably true, right, because these things are pretty widespread in the plant kingdom, but quercetin is actually named after oak trees, quercus is the oak genos. And, white onions would be another area that quercetin is well-known to be in relatively high amounts. But, in something like onions, it aggregates that basically the things we throw away when we tend to cook with onions, the skins, the bottom part, the statins, that type of thing. Same with fisetin, fisetin would tend to aggregate much more in outer parts of plants, leaves, things like that. So, I was reading recently about the Dutch Famine from World War II, and one of the things that mentioned in that was that because of that, people were eating tree bark, leaves, grass. Those are classically famine foods that no one would choose to eat, but they're used to during famines to get something. 

And so, my guess is that these things this like fisetin, quercetin, so again quercetin would also be in bark of trees as an example, is that they're sending almost a famine message when we really drastically increase the amount in our diet like we would in the amounts that are used as senolytics and then causing this nutrient signaling pathway, this PI3K, AKT, mTOR to basically say, okay, the environment is really bad, I need to prioritize getting rid of cells that aren't that important. And, senescent cells are the things most sacrificed.

Ben:  Interesting. Okay. So, you have fisetin and quercetin both in the senolytic. Can you mention one other polyphenol-like compound? What was it?

Gregory:  Luteolin.

Ben:  Luteolin.

Gregory:  So, luteolin. And, all of them have in common that they're really yellow. So, one thing people notice if they take Qualia Senolytic, the capsules are transparent and they're this really pretty light yellow color. And, fisetin, quercetin, and luteolin, they're all very yellow pigments.

Ben:  Yeah, yeah. When I interviewed Dr. Mercola at one point, he was telling me about this so-called autophagy tea that he'll drink at night and he has a few different compounds in there including one special form of tea bark called Pau D'Arco, which is a precursor to any NAD. But then, he mentioned now he actually has a lot of these, I think, it was quercetin and fisetin were included in there as something that he takes in the evening to enhance autophagy. So, these are acting on multiple mechanisms of aging including that fasting-mimicking type of strategy that you were talking about earlier. You also list along with the quercetin, the fisetin and the luteolin that you have in the compound soybean seed extracts. Not a lot of people in the health sector are, of course, concerned about soy. They think it might give them man boobs or cause excess estrogen or something like that, but fill me in on why you would include soybean seed extract in there and whether or not that could be concerning for some people?

Gregory:  The extract we use is standardized for soy isoflavones. And, in a single dose, it would be about twice the daily dose that someone following say a Japanese diet would normally get. And, the reason we have soy isoflavones in there, milk thistle as well, goes back to really think almost mechanisms. So, originally when the Mayo Clinic and Scripps were trying to figure out what compounds might cause cells, that were senescent, to go through this falling-off process, they looked through the research and said, okay, well, these are candidates. They look mechanistically. They'll act on, again, maybe that pathway I just mentioned, that PI3K, AKT, mTOR. So, you have your fisetin, luteolin, quercetin act on that pathway. But then, they also looked at other pathways: tyrosine kinases, specifically SRC3, kinase, another grouping called [00:55:33] _____. And, those things also can prompt the cell to go from deciding to linger to choosing to go through this apoptosis pathway.

And so, what we did was on the Neurohacker Collective science team side was something very similar. We were like, “Okay, are there compounds that aren't being used as senolytics but that do some of these same mechanisms that would be complementary with things like quercetin and fisetin and the soy isoflavones and the milk thistle?” And, for people that are concerned about man's moods, soy isoflavones, again, it's just two days a month. So, one, I think, it's way overexaggerated that these things especially in dietary amounts are problematic, but it's again part of the idea Qualia Senolytic is we're just doing this two days a month. So, for someone concerned about taking soy isoflavones consistently in the diet, that would be a very different concern than just taking a dose of them twice a month.

Ben:  Okay, got it. And, you kind of chunk your ingredients into three categories: Adaptogens, polyphenols and herbal tonics. We just covered the polyphenols, the fisetin, the quercetin, the soybean seed extract, and luteolin as four things that have been studied as senolytic agents.

And then, for adaptogens, that Senactive, that ginseng that we talked about earlier, that falls into that category, what other adaptogens are you including?

Gregory:  Well, I think we categorized the piper longum extract into that bucket as well. So, piper longum is a really interesting plant. Before becoming a naturopathic doctor, I did a master's degree in Southeast Asian studies, so specifically, Thailand was my area of expertise and my degree. I focused a lot on medical and nutritional anthropology. And, the Thai traditional medical system borrows heavily from ayurveda because when Buddhism came from India to Thailand, they brought ayurveda with it as well. And, one of the classic trilogies of ingredient stacks in ayurveda but also in Thai tradition medicine, and it's the combination of ginger with black pepper and with long pepper. And, now some of the role, we would think of those things as bioenhancers, things that make other things work a bit better. But, long pepper of those three is the one that's least known in the U.S., as an example, but widely used in ayurveda as something that would be rasayana.

Ben:  What'd you call it, rasayana?

Gregory:  Yeah. So, it's akin to how we think of adaptogens but it would more translate as a rejuvenator. And, one of the interesting things about piper longum is, one, it tastes a lot like black pepper. I mean, the seeds could be almost used interchangeably except long pepper is even more pungent. And, the reason is because it has something called piperlongumine that's not found in black pepper. And, it turns out that piperlongumine is also senolytic, but in different tissues than where quercetin and fisetin have been shown to be senolytic at this point. It's been in things like, as an example, intervertebral discs, joints, things like that where it's much more active.

Ben:  That's interesting. I didn't know there was a difference between bioperine and piperlongumine because a lot of times you'll see bioperine combined with things like turmeric or curcumin to enhance the absorption. But, it sounds to me like what you're saying is piperlongumine could do the same thing but it's also potentially a senolytic compound.

Gregory:  Yeah. Piperine is the generic word for that. So, long pepper like black pepper and some other piper species will also have the bioperine type of molecule like piperine. Piperlongumine would be a different alkaloid and distinctive to the piperlongum plant. And, maybe not a bioenhancer but doing completely different things. So, it looks like it helps, again, that idea of xenomorphic, toughen-up cells so that they wouldn't become zombified by nearby neighbors but also it's senolytic in different ways than some of these other compounds and in potentially different tissues.

Ben:  What form of turmeric or curcumin are you using?

Gregory:  So, we use a branded turmeric called Longvida. And, Longvida is interesting. So, one of the challenges with a lot of these compounds is bioavailability. Polyphenol is just, in general, you could say have low bioavailability. One of the things that can help increase them is when more are given together, they tend to sneak more past the gut in the liver that way. But, another is when specific compounds are made to be more bioavailable. So, neuroscientists at one point and I think it was at UCLA, but it was one of the California studies created Longvida curcumin as a way to be a more bioavailable curcumin. And specifically, they, in their original research, targeted the brain and cognitive performance. So, we opted for that in part like Neurohacker Collective, we love things that have been studied in the brain. But, Longvida is they, I think, branded as the cognitive curcumin of choice and optimized turmeric. But, it's one of the more bioavailable forms of curcumin.

Ben:  Speaking of the brain, do you use that in your other Qualia product, the Qualia Mind or any of your nootropics?

Gregory:  In the original, we call it OG Qualia or two-step, which I know you took back in the day. We used curcumin in that, but I think that was Mareeba if I recall correctly what we were using at that point, which is another really good one. But, Mareeba is the one that's typically combined with the bioperine as of the way that increases absorption and bioavailability. The advantage of Longvida is you don't need to do the bioenhancer with it.

Ben:  Okay. And then, you've got the other category. You have the polyphenols, then you have the ones that we just talked about, are those the adaptogens?

Gregory:  Yup.

Ben:  Okay. And then, what's the last category that you have olive leaf extract and milk thistle and stuff like that?

Gregory:  I don't remember how we categorized it. I think we like, tonic herbs. Again, those are interesting. So, olive leaf, as an example. And, I know you're a big fan of olive oil. I've heard you mentioned that on your podcast and seen it in vlogs multiple times. So, all is really cool because it has these unique polyphenols. The leaf tends to have more of one fruit, a bit more of another. The oil is going to have both in some amounts. But, the one that's specifically in the leaf in a higher proportion has again shown senolytic potential in tissues where some of these other polyphenols were not active. So, I tend to go back to that original the dasatinib and quercetin study where it's important to support multiple tissues with potentially different compounds that have senolytic activity in a broader base of compounds if we want to target how in more different tissues. That's the reason that the olive leaf is in there.

Ben:  By the way, related to the olive leaves, just real quick, it reminds me of Rudolph Steiner's whole anthroposophy or anthroposophy where he talks about how when you're consuming plants particularly, if you can get the root, the leaf, and the fruit, you're going to get different components that target different parts of the body like the organs, I think, might correspond to the roots and the leaves to the appendages and the fruits to the reproductive organs or something like that. But, basically what you're saying is if I'm consuming, let's say, extra virgin olive oil, I'm getting a lot of the fruit component of the olive tree. But, if I were to take all of leaf extract, I'm going to get a different profile of polyphenols and some of the things I wouldn't be getting from the extra virgin olive oil.

Gregory:  Correct, you'd get much more oleuropein, I'm probably mispronouncing it, is in much higher amounts in the leaves and much lower amounts than the fruits and oil. So, you'd still get some but a much lower dose than would trigger these nutrient sensing pathways to kind of do the short-term fasting-mimicking to get a senolytic activity.

Ben:  Okay, got it. I also noticed that that you have milk thistle in there. Milk thistle is something you'll find a lot of hangover remedies and liver detoxification remedies, but why'd you'd include it in a senolytic formula?

Gregory:  Yeah. So, milk thistle, I mean, I think it's in European traditional herbal medicine, has been used for since going back to the Romans as a liver tonic. But again, we included it largely for the same reason we picked something like the soy isoflavones, the soybean seed extract. And, it's because it does things in these–so, I guess going back to the idea of why does a cell stay senescent, right? Why wouldn't it after it's frozen and then, like I said, in wound healing, post-exercise in a young person within a week, these things have been cleared out. So, why hasn't some subset of these cells been removed? And, one of the frameworks I've seen at least in one review article was think in terms of removable and non-removable senescent cells. It's the non-removable ones that are problematic as we age. The removal ones did their job and now they've disappeared.

So, what makes these cells non-removable? And, part of it is their ability to resist this falling off process, resist apoptosis. And, they do that with a combination of things. There's incredible redundancy built into physiology. So, one of the things they're often described as pro-apoptotic and anti-apoptotic proteins.

Ben:  Pro-apoptotic and anti-apoptotic.

Gregory:  Yeah. And, it's a family called the BCL-2 box family. And, at any given point in time, cells would have both expressed, it's the relative amounts that would choose the cell's fate like, should I proceed through this journey to falling off or am I healthy enough? So, you have those proteins. And then, you have signaling pathways like we've talked about that can tip the balance and say, okay, the environment looks like it's more famine nutrient signaling cascade shift towards this pro-apoptotic. And then, you have other pathways that are also influenced by these, I mentioned tyrosine kinase. So, one of the things that milk thistle does is mechanistically it works on a subfamily of tyrosine kinases that are important in shifting the balance towards saying, okay, weighing things out, it looks more like a famine let's go through apoptosis.

Ben:  Okay.

Gregory:  But, in a different way than quercetin or fisetin or some of these things. In a way, may be more analogous to what dasatinib would do. It's not really a dasatinib mimic, it's a really healthy liver tonic herb. But, mechanistically, it would be doing something more akin to what that does than what the polyphenols are doing.

Ben:  Okay, that makes sense.

So, with this whole range of ingredients that are targeting multiple pathways of limiting or clearing senescent cell accumulation, you guys at Neurohacker, I've noticed you kind of tend to have a shotgun approach, like you'll take all the stuff that's good for the brain and acts as a nootropic and put it in Qualia Mind, just put it all together as one mighty capsule or whatever, same thing with this senolytic formula. Do you guys ever get called out on the fact that, well, nobody's ever proven that all this stuff put together might not interact with each other in some deleterious way or something like that?

Gregory:  Yeah. So, I think that's fair and it's one of the reasons that Neurohacker Collective before, I guess, stepping back our process is first create a hypothesis. Try to understand the system, the mechanisms, things that may help restore homeostasis where it would be prudent or provide a resource that's limited not enough choline and in the diet for many people. So, you'll see a couple brain bioavailable choline sources in Qualia Mind like the alpha-GPC, citicoline as an example. So, that's step one. Then, step two is we build it and try it ourselves. That's our kind of initial proof of concept. And then, if at that point it seems like the safety and tolerability is fine, then we'll do some type of a pilot study. We'll make a small batch of it, recruit volunteers, and then have them take a product. And, only if it passes both safety and tolerability at that stage and seems beneficial based on whatever we're measuring typically. Again, we'll often use subjective questionnaires would we move a product to market and sell it to the wider public. So, because of that, I feel like compared to most supplement companies, we have a bunch of safety and tolerability built in that a lot of other companies would never know about when they're combining multiple things together until after it was already being sold to people.

Ben:  Yeah, yeah. So, if somebody were to get their hands on this stuff, this senolytic, and I'll put links in the shownotes at BenGreenfieldLife.com/Senolytic, and take it on a couple of day. About how many months in, I've taken it two days out of every month, would you start to notice stuff? Or, is this more one of those things where you're just keeping your fingers crossed it's going to help you live a long time?

Gregory:  So, I think it's going to depend on someone's health. That's what we've seen so far. In general, I would say three cycles is what I would recommend taking. We've seen some people in our small studies and some customers, some people I know like friends, family that have taken it that have noticed something within one two-day dosing cycle. Often something that's been kind of a nagging type of annoyance issue, musculoskeletal very commonly. So, again, the idea with senescent cells is this idea of a threshold effect, below a certain threshold in tissues. They may be there. They're not probably doing anything beneficial if they're lingering, but there's not enough equivalent of yellow leaves on the plant yet that the whole plant function is being jeopardized. We would still probably want to prune those away, but we may not be noticing anything because the threshold is low. We still want to keep it low. We still want to periodically prune away the equivalent of these yellowing leaves in our tissues. If it's already above that threshold in a tissue, then reducing it below that often you'll see a big change in some active, some subjective area. And so, because of that, there's just not one way that someone would experience it and someone like you that does all kinds of things to stay resilient, stay healthy. I mean, my expectation is you wouldn't notice anything. It would be more just the concept of, oh, I'm going to be a good gardener and prune away some things before they become problematic where someone that's already having issues with things related to say immunosenescence like immune cells that have been senescent, issues with areas of musculoskeletal. They're much more likely to notice something and notice it quickly.

Ben:  Yeah. I was reading some of the reviews on your website about some people felt their mind got a little bit more clear, other people felt they were recovering faster, somebody else said they had just had less joint aches and pains. I don't know how many cycles these people took. But, just the idea of taking it two days out of every month, to me, it's pretty simple. It's not super expensive. What is it, like 40 bucks for your first box and 70 bucks after? And, I think we have some kind of a discount code too, but it's not a super duper expensive supplement like some of these other stacks.

Gregory:  The truth is when we first made it, we're kind of on the nerdy end, Nuerohacker Collective, and in that biohacker niche. And, the truth is we made this thinking, okay, we really want to take it. There's just not something out there that we think would be as useful as the product that we could put out. And so, we really honestly weren't expecting it would sell particularly robustly, we were making this for a niche audience is how we thought of it, maybe some doctors in the longevity space, a subset of biohackers. And, to our surprise within four weeks, the product completely sold out. I think we launched the end of June 2022. And, what we think is that, one, there's not a lot that competes with it, but two, the idea of just having this product that you take two days a month is so easy to integrate for a person that's used to having to juggle taking a whole bunch of things every day. So, that idea of the hit-and-run dosing, the intermittent nature of it just makes it so easy to do is what we found in our customer response today.

Ben:  Yeah, yeah. Well, it seems like a pretty well-formulated product. And again, I think we do work with Neurohacker to get you guys some kind of a discount on it that is above and beyond what you'll find on the website. So, I will hunt that down and put it in the shownotes at BenGreenfieldLife.com/Senolytic. If you're over there shopping around on their website and you got a little bit extra cash burning hole in your pocket, that Qualia Mind stuff, the caffeine free version mostly just because I like to have a cup of coffee or tea that's caffeinated in the morning and I don't want to over caffeinate myself is another one that I like quite a bit. So, that'd be one of their other products that's in my pantry. So, it's just called senolytic, right Gregory?

Gregory:  Yeah, Qualia Senolytic.

Ben:  Qualia Senolytic. Alright, cool. Well, I'll link to all this at BenGreenfieldLife.com/Senolytic, S-E-N-O-L-Y-T-I-C. Over there, you can also leave your comments, your questions, your feedback for me or for Greg and leave your own thoughts on senescent cells and anything else that you're curious about that we didn't cover in today's show. In the meantime, Gregory, thanks so much for coming on the show and sharing with us all things senescence.

Gregory:  My pleasure. Thanks for having me today, Ben.

Ben:  Awesome. Alright, folks, I'm Ben Greenfield along with Gregory Kelly signing out from BenGreenfieldLife.com. Have an amazing week.

One thing you should know that's super cool is that on the evening of March 11th in Sedona, I'm hosting a VIP dinner that's catered by me and my family using a bunch of biohacked recipes from my “Boundless Cookbook,” live music and intimate Q&A, and an absolutely unforgettable once in a lifetime taste bud entertaining experience where you just come and hang out with me. So, we're hosting at our house with only 25 seats available, so things are going to fill up fast, it's a VIP dinner, only a select few. We want to keep this small, intimate, but super fun with amazing food. So, if you want to get on the VIP dinner as a part of this event that I'm doing down in Sedona, go to BenGreenfieldSpeaking.com/Sedona-dinner, BenGreenfieldSpeaking.com/Sedona-dinner. 

More than ever these days, people like you and me need a fresh entertaining, well-informed, and often outside-the-box approach to discovering the health, and happiness, and hope that we all crave. So, I hope I've been able to do that for you on this episode today. And, if you liked it or if you love what I'm up to, then please leave me a review on your preferred podcast listening channel wherever that might be, and just find the Ben Greenfield Life episode. Say something nice. Thanks so much. It means a lot.

 

 

Everyone wants to slow down the signs of aging, but very few people are going about it the right way.

The negative aspects of aging are one of the most ubiquitous challenges to quality of life. However, one thing is for sure: scientists believe that a big part of the reason we experience aging the way we do is because of stressed or worn-out cells called senescent cells.

Senolytics is a term used to describe ingredients shown to help decrease these damaging senescent cells. A well-formulated senolytic's goals are similar to those of pruning a plant: support efficient use of cellular resources, encourage the regeneration of more youthful cells, and ultimately support tissue health and appearance—promoting whole-body cellular rejuvenation.

Since senescent cells are experts at surviving, a senolytic formula can't rely on just a single ingredient to deliver results. Instead, a multi-pronged approach helps give the body the best opportunity to reduce its senescent cell load. My guest on this show – Gregory Kelly – has helped to develop several rare and powerful compounds that have scientifically shown senolytic activity, and which collectively cover a broader range of mechanisms than existing senolytic supplements on the market.

His protocol, which we discuss on this show, involves a two-day rejuvenation regimen that he suggests using every month. Intermittent short-duration dosing is the most common way that senolytics are used in studies, and data suggests that it can take weeks for senescent cells to re-accumulate in the body, which is why Greg recommends this approach.

Greg's compound, called “Senolytic” and made by my friends at Neurohacker Collective, includes the following senolytic ingredients:

• Fisetin (from Rhus succedanea Stem Extract): Supports tissue health by helping with pruning of stressed cells
• Quercefit® Quercetin Phytosome (Sophora japonica L. Flower Extract / Phospholipid Complex from Sunflower): Supports tissue health by helping with pruning of stressed cells*
• Longvida Optimized Curcumin® Extract (from Curcuma longa Root): Supports brain health and cognitive function*
• Olive Leaf Extract: Supports management of stressed cells in joints*
• Soybean Seed Extract: Supports healthy cellular functions involved in managing stressed cells*
• Luteolin (from Sophora japonica L. Flower Extract): Supports tissue health by helping with pruning of stressed cells*
• Milk Thistle Seed Extract: Supports liver health and management of stressed cells*
• Piperlongumine (from Piper longum Root Extract): Supports senolytic and immune functions to help manage stressed cells*
• Senactiv® (Panax notoginseng Root Extract and Rosa roxburghii Fruit Extract): Supports exercise recovery and management of senescent cells in muscle

So who is Greg, exactly?

Dr. Gregory Kelly, a highly accomplished naturopathic physician (N.D.), has an extensive background in natural medicine and nutrition. As the Director of Product Development at Neurohacker Collective and author of the book Shape Shift, Dr. Kelly has made significant contributions to the field. He has also taught Advanced Clinical Nutrition, Counseling Skills, and Doctor-Patient Relationships at the University of Bridgeport in the College of Naturopathic Medicine, and was the editor of the journal Alternative Medicine Review. With numerous articles and more than 30 journal articles indexed on Pubmed, Dr. Kelly is a leading authority in areas such as nootropics, anti-aging and regenerative medicine, weight management, and the chronobiology of performance and health.

During our discussion, you'll discover:

-Who is Dr. Gregory Kelly?…06:38

• Cellular senescence
• Neurohacker Collective (use code BGL to save 15% off any purchase)
• Podcast with Daniel Schmachtenberger:
  • 42 Different Ways To Build A Better Brain, The Problem With Modern Smart Drugs, Hacking Your Neurons & More.
• Shape Shift by Dr. Gregory Kelly
• Senescent cells = Zombie cells
  • Cells that haven’t died and can turn other cells into senescent cells
• Senescent cells = yellowing leaves that need to be removed from the garden is a more appropriate metaphor

-The science behind cellular senescence…10:19

• Hayflick’s 1961 study: cells stop dividing after 50 times – the Hayflick limit
• 1970's – idea of telomeres was identified
  • Shortening of telomeres over time as cells copied themselves and would eventually run into the Hayflick limit
  • Cellular senescence is a natural and prominent part of aging
• DNA damage response
• Cellular senescence as an anti-cancer mechanism
• Embryogenesis and placental aging
• Wound healing
• Beneficial senescent cells and lingering ones that cause problems
• The Science of Senolytics

-The best use of senolytics…19:52

• Use a few times during the year
• The Longevity Diet by Dr. Valter Longo
• Dr. Valter Longo
• Autophagy – removes senescent cells
• Fasting mimicking diet
• Qualia Senolytic by Neurohacker Collective (use code BGL to save 15% off any purchase)
• Senolytics mimic short periods of fasting
  • Only for short periods
• The idea of senolytics was coined by Mayo clinic, Scripps Research Institute, in 2015
  • The original stack they identified was Dasatinib and Quercetin (D&Q)
  • Induce cells to go through apoptosis, to fall off like leaves
  • Finding a way to make them stop resisting apoptosis
• D&Q stack
  • Side-effects
  • Hit and run dosing
• Rapamycin and Metformin
  • Senotherapeutics
    • 1st leg – Senolytics
    • 2nd leg – Senomorphics, sometimes called senostatics
    • 3rd leg – The immune system
  • More senomorphic than senolytic
  • Helping cells near senescent cells not to become senescent

-Other strategies that can limit senescence…29:40

• Very few strategies are studied
• Lots of things could cause premature senescence
  • Stress induced premature senescence
  • Make cells more stress resilient
• Buck Institute is one of the leading researchers in cellular senescence and senolytics
• DNA repair and autophagy
• Practicing habits that reduce stress
• Tissue autopsy needed to monitor senescent cells and tissues
• Jinfiniti
  • Blood panel:
    • Beta-galactosidase
    • inflammatory cytokine markers in the blood
    • NAD
• Not having enough NAD is one of the things known to cause premature cellular senescence

–Qualia Synolytic…47:48

• Daily dose of 6 capsules for 2 days out of the month every month
• Pilot study:
  • 3 cycles over the course of a month – 2 days on, 12 days off, 2 days on, 12 days off
• Slowest amount I would recommend – two days once a quarter
• Consensus is that DNA methylation is not a useful way to measure senescent cells
• WOMAC scale (Western Ontario and McMaster Universities Arthritis Index) – an osteoarthritis scale
• Recruit people and measure performance of Qualia Senolytic (use code BGL to save 15% off any purchase)
  • Positive results in areas of
    • Energy
    • Emotional well-being
    • Stress in general
• Threshold effect – senescent cells can impact different people differently

-Polyphenols in the formula…52:39

• Qualia Senolytic ingredient Senactiv®
  • Notoginseng
  • Sweet rose chestnut extract
• Fisetin and Quercetin
• Dutch famine of World War 2 – people were eating tree bark, leaves and grass
  • High level of quercetin in oak tree, white onions (skin and bottom part)
  • Fisetin is found much more in outer parts of plants, leaves
• Luteolin
• Dr. Mercola’s “autophagy tea” – nightly fast to limit mTor activation and increase autophagy
  • 1 tsp Pau d’ Arco powdered tea
  • ½ tsp hydroxycitrate and garcinia (HCA/Garcinia powder)
  • ½ tsp quercetin powder
  • ½ tsp glycine powder
  • ½ teaspoon chamomile powder
  • Lakanto monk fruit sweetenerto taste
• Podcast with Dr. Mercola:
  • KetoFasting: The Dark Side of Fasting & Ketosis (+How To Use Cyclic Ketosis To Fix The Issues)
• Concerns about soybean seed extract

-Adaptogens in the formula…1:05:57

• Piper longum (long pepper) – tastes a lot like black pepper but more pungent (because of piperlongumine)
  • MA in South East Asian studies focused on medical and nutritional anthropology
  • Ayurveda and Thai medicine trilogy of ingredient stacks
    • Ginger
    • Black pepper
    • Long pepper
  • Rasayana or rejuvenator
  • Piperlongumine is also a senolytic
• More bioavailable Turmeric and Curcumin (Longvida brand)
• The original Qualia Mind, OG Qualia used Mareeba
• Mareeba needs bioperine to enhance absorption and bioavailability, Longvida does not

-Tonic herbs in the formula…1:09:55

• Olive leaf
  • Rudolf Steiner
  • Getting different components of compounds from the root, the leaf, and the fruit of plants
• Milk thistle
  • Used as a liver tonic since Romans
  • Works on tyrosine kinases that are important in shifting the balance towards apoptosis

-The efficacy of senolytics…1:16:30

• A shotgun approach
• The process of creating the product
  • Safety, tolerability, and efficiency
• Experiencing the effects would depend on someone’s health
• Simple dosing – 2 days a month
• Qualia Senolytic (use code BGL to save 15% off any purchase)

-And much more…

Upcoming Events:

• Shine Event / VIP Dinner: March 10th – March 12th

I want to personally invite you to an intimate VIP dinner experience with my family and I in beautiful Sedona, Arizona. I'll be in AZ during that time presenting as a keynote speaker at the Breath, Body & Beyond ‘Shine' event from March 10th to the 12th, and I'd love to see you there for my formal dinner on the 11th. At this dinner, you'll be presented with an exquisite home-style dinner personally prepared by the entire Greenfield family, a free signed copy of Boundless Cookbook, a personalized Q&A with me, and entertainment by local vocal artist and my younger sister, Aengel Greenfield. Learn more here.

• Keep up on Ben's LIVE appearances by following bengreenfieldfitness.com/calendar!

Resources mentioned in this episode:

– Dr. Gregory Kelly:

• Qualia Senolytic (use code BGL to save 15% off any purchase)
• Shape Shift by Dr. Gregory Kelly

– Podcasts:

• 42 Different Ways To Build A Better Brain, The Problem With Modern Smart Drugs, Hacking Your Neurons & More.
• KetoFasting: The Dark Side of Fasting & Ketosis (+How To Use Cyclic Ketosis To Fix The Issues)

– Other Resources:

• The Longevity Diet by Dr. Valter Longo
• Buck Institute
• Jinfiniti
• NAD Regen
• Pau d’ Arco Powdered Tea
• HCA/Garcinia Powder
• Quercetin Powder
• Glycine Powder
• Chamomile Powder
• Lakanto Monkfruit Sweetener
• Dr. Valter Longo
• Rudolf Steiner
• Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan
• Senotherapeutics For Healthy Ageing
• Senotherapeutics: Emerging Strategy For Healthy Aging And Age-Related Disease
• Targeting Senescent Cells: Approaches, Opportunities, Challenges

Episode sponsors:

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Boundless Parenting: Everything you need to know about family, parenting, and raising healthy, resilient, free-thinking and impactful children. Go to boundlessparentingbook.com and pre-order your copy now.

BGL Careers: We're hiring! Check out our open position at BenGreenfieldLife.com/Careers to see if you are aligned with helping us push our mission forward.

Shine Sedona: Join my family and me in Sedona Arizona from March 10-12, 2023 at an amazing event hosted by SHINE. I'll be giving a keynote talk on breathwork and biohacking, and hosting a VIP Greenfield-style home-cooked dinner prepared by my family. For tickets to the Shine Event where I'll be a keynote speaker visit bengreenfieldlife.com/shinesedona.  To book your spot for our VIP dinner visit bengreenfieldspeaking.com/sedona-dinner.